Obesity and its complications are a major health concern in the US and other industrialized nations. Based on the coincident increase in industrial chemical production and the meteoric rise in body weight in recent decades, a mechanistic connection between increased chemical exposure and the obesity 'epidemic'in industrialized nations has been postulated. Bisphenol A (BPA) is a ubiquitous estrogenic endocrine-disrupting chemical used in polycarbonate plastics and epoxy resins commonly found in food and beverage containers, and it is also present in countless other items that we come into contact with daily. BPA has been detected in the urine of 93% of the US population examined with the highest levels detected in the youngest cohort studied, children between 6 and 12 years of age. Data from our laboratory reveal a dose-dependent effect of perinatal BPA exposure on body weight and adiposity in CD-1 mice. However, neither the cause of BPA- associated weight gain nor the pathologic metabolic sequelae of this weight gain are currently elucidated. This proposal seeks funds to test the hypothesis that early life exposure to BPA promotes adult-onset obesity and hallmarks of the Metabolic Syndrome in CD-1 mice by altering energy metabolism in key metabolic tissues. Goals of the proposed research are to 1) determine the internal dose associated with BPA exposure levels that promote adult onset obesity and its complications, 2) determine the relative impact of perinatal vs. combined perinatal and prepubertal BPA exposure on risk for adult-onset obesity, 3) test the hypothesis that early BPA exposure exacerbates the obesitogenic and metabolic impacts of eating a 'western" diet (i.e., high in saturated fats), 4) test the hypothesis that BPA promotes obesity by altering relevant metabolic pathways in adipose tissue and skeletal muscle, and 5) identify BPA-associated transcriptional and epigenetic changes that underlie altered metabolic rate and/ or promote obesity-associated pathology in BPA-exposed mice. The proposed studies are highly collaborative, involving the integrated efforts of five investigators with distinct but complementary expertise in BPA, obesity and metabolism, diabetes, gene profiling, and epigenetics. Successful completion of the studies in this grant application will provide the first comprehensive and integrated study of how early life BPA exposure promotes adult obesity and its associated complications. These studies will identify the molecular, cell biological, and physiological mechanisms involved in the action of BPA on body weight and in so doing, these studies are likely to contribute to public health policy decisions concerning BPA. PUBLIC HEALTH RELEVANCE: Bisphenol A (BPA), is a ubiquitous chemical used in plastics and commonly found in food and beverage containers. Preliminary studies in our lab have revealed a dose- dependent increase in body weight in rodents exposed to BPA early in life. This proposal will further investigate the potential for BPA to promote obesity in adulthood.